title: Orexin receptor 2 expression in the posterior hypothalamus rescues sleepiness in narcoleptic mice.
abstract: Narcolepsy is caused by a loss of orexin/hypocretin signaling, resulting in chronic sleepiness, fragmented non-rapid eye movement sleep, and cataplexy. To identify the neuronal circuits underlying narcolepsy, we produced a mouse model in which a loxP-flanked gene cassette disrupts production of the orexin receptor type 2 (OX2R; also known as HCRTR2), but normal OX2R expression can be restored by Cre recombinase. Mice lacking OX2R signaling had poor maintenance of wakefulness indicative of sleepiness and fragmented sleep and lacked any electrophysiological response to orexin-A in the wake-promoting neurons of the tuberomammillary nucleus. These defects were completely recovered by crossing them with mice that express Cre in the female germline, thus globally deleting the transcription-disrupter cassette. Then, by using an adeno-associated viral vector coding for Cre recombinase, we found that focal restoration of OX2R in neurons of the tuberomammillary nucleus and adjacent parts of the posterior hypothalamus completely rescued the sleepiness of these mice, but their fragmented sleep was unimproved. These observations demonstrate that the tuberomammillary region plays an essential role in the wake-promoting effects of orexins, but orexins must stabilize sleep through other targets.
authors.affiliation: Department of Neurology and Division of Endocrinology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Takatoshi
authors.initials: T
authors.lastname: Mochizuki
authors.forename: Elda
authors.initials: E
authors.lastname: Arrigoni
authors.forename: Jacob N
authors.initials: JN
authors.lastname: Marcus
authors.forename: Erika L
authors.initials: EL
authors.lastname: Clark
authors.forename: Mihoko
authors.initials: M
authors.lastname: Yamamoto
authors.forename: Michael
authors.initials: M
authors.lastname: Honer
authors.forename: Edilio
authors.initials: E
authors.lastname: Borroni
authors.forename: Bradford B
authors.initials: BB
authors.lastname: Lowell
authors.forename: Joel K
authors.initials: JK
authors.lastname: Elmquist
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Scammell
mesh_terms: D000818:Animals; D000954:Antigens, Surface / Q000378:metabolism*; D000229:Dependovirus / Q000235:genetics; D055724:Electrophysiological Phenomena / Q000187:drug effects; D005260:Female; D007026:Hypothalamic Area, Lateral / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D007031:Hypothalamus / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D019426:Integrases / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000494:pharmacology; D051379:Mice; D008822:Mice, Transgenic; D008845:Microinjections; D009290:Narcolepsy / Q000473:pathology / Q000503:physiopathology* / Q000517:prevention & control*; D009479:Neuropeptides / Q000494:pharmacology; D064446:Orexin Receptors; D000068797:Orexins; D011956:Receptors, Cell Surface / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D012890:Sleep / Q000187:drug effects / Q000502:physiology*; D014158:Transcription, Genetic / Q000187:drug effects; D014851:Wakefulness / Q000187:drug effects / Q000502:physiology
chemical_list: D000954:Antigens, Surface; C501103:Cd200r1 protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D009479:Neuropeptides; D064446:Orexin Receptors; D000068797:Orexins; D011956:Receptors, Cell Surface; C045073:Cre recombinase; D019426:Integrases